Marijuana (MJ) remains the most widely used illicit substance, with more than 16.7 million past month users. While the number of people who smoke MJ continues to rise each year, the average age of first regular use continues to fall, as does the percentage of individuals who perceive the use of MJ as risky or dangerous. This is perhaps not surprising in light of the ongoing debate regarding legalizing marijuana and the use of medical marijuana. Several investigations have reported alterations in chronic, heavy MJ smokers on frontal/ executive measures of cognitive performance, patterns of cortical activity as measured by functional magnetic resonance imaging (fMRI), and on measures of white matter microstructure relative to non-smoking control subjects. However, few have directly examined the neurobiologic impact of age of onset of MJ use in conjunction with these measures or the possibility of recovery of function following an extended period of abstinence. Our recent work highlighted the impact of age of onset of MJ use on both frequency and magnitude of MJ use, and found 1) significantly higher total number of smokes and amount (grams) of MJ smoked per week, 2) significant decreases in executive function and 3) alterations in brain activation patterns in early vs. late onset smokers. We have also reported alterations in diffusion tensor imaging (DTI) measures of frontal white matter which correlated with measures of impulsivity. We propose a novel experimental design that examines the extent to which age of onset of first regular MJ use is associated with decrements in executive function, alterations in neural function and microstructural white matter measures in chronic heavy MJ smokers who are defined as early onset (1st regular use prior to age 16) or late onset (1st regular use after age 16). We will also examine the potential for recovery of function by examining a group of former heavy MJ smokers who have abstained from use for a minimum of 2 years and a group of non-MJ smoking control subjects. We will apply BOLD fMRI and DTI to measure differences in brain activation and white matter fiber tract integrity in young adult subjects (18-30 years) with chronic, heavy MJ use who started smoking early, late or are former heavy MJ smokers or controls, and administer a battery of neurocognitive measures of executive function, as well as measures of clinical state, impulsivity, and personality. The proposed series of experiments utilizes an innovative combination of imaging techniques and neurocognitive tasks to collect key information that could ultimately identify biomarkers for vulnerability to MJ abuse or dependence. In addition, data regarding recovery of function following extended abstinence could be used to modify current public service messages and increase public awareness; the this is your brain, this is your brain on drugs message could be amended to include a message of hope - and this is your brain after you stop using drugs which may facilitate treatment strategies for those under the impression that the damage is already done. . PUBLIC HEALTH RELEVANCE: Marijuana (MJ) remains the most widely used illicit drug with more than 16.7 million past month users, and while the number of people who smoke MJ rises each year, the average age of first regular use continues to fall, as does the percentage of people who think of MJ as risky or dangerous. Chronic, heavy MJ smokers have impaired cognitive abilities and altered brain activity and structure, but it is unknown how age of onset of MJ use actually impacts these measures and importantly, if they recover after smoking stops. Data from this study will document the effects of MJ exposure during a period of developmental vulnerability on brain structure and function, and reveal possibilities for recovery following abstinence that may allow us to modify current public service messages and increase public awareness; the this is your brain, this is your brain on drugs message could be amended to include a message of hope - and this is your brain after you stop using drugs which may facilitate treatment strategies for those under the impression that the damage is already done.